Chronic inflammatory disease such as psoriasis is a prevalent skin disease characterized by circumscribed red patches covered with white scales. The symptoms ranges from minimal lesions of the elbows and knees to a large number of lesions scattered over the skin. Current therapy of psoriasis includes topical administration of corticosteroid with the dosage forms of cream, ointment, and lotion.
U.S. Pat. No. 5,990,100 (the '100 patent) discloses isopropyl myristate as an active agent for treating psoriasis. The '100 patent further discloses the combined use of isopropyl myristate and an anti-psoriatic agent to form a more effective composition in treating psoriasis than either agent alone. Specifically, example 1 of the '100 patent discloses a formulation containing 40 wt % isopropyl myristate, 0.1 wt % sodium lauryl sulfate, 1.5 wt % polysorbate 80, 3.4 wt % water and 55 wt % ethanol. According to the '100 patent, topical application of the aerosolized formulation containing isopropyl myristate followed by topical application of calcipotriol ointment, desonide ointment or fluocinolone acetonide powder are more effective in treating psoriasis than either agent by itself.
U.S. Pat. No. 5,776,433 (the '433 patent) discloses an aerosolized flunisolide formulation useful in the treatment of inflammation of the nasal mucosa. In the '433 patent, hydrofluorocarbons is used as the propellant in a metered dose aerosol system containing a microcrystalline suspension of a steroid (i.e., flunisolide hemihydrate), propylene glycol, polyethylene glycol 3350, citric acid, sodium citrate, butylated hydroxyanisole, edetate disodium, benzalkonium chloride, and purified water. The '433 patent discloses that ethanol functions to solubilize the flunisolide, and the presence of water enhances to stabilize flunisolide. The '433 patent suggests the use of propellant to propel a plurality of flunisolide doses. While the '433 patent suggests the use of glass aerosol vial or aluminum aerosol vial having an interior chamber coated with an inert resin, it remains silent as to the agent(s) that may affect flunisolide stability.
U.S. Pat. No. 6,610,273 (the '273 patent) and U.S. Pat. No. 6,315,985 (the '985 patent) disclose that 20-ketosteroids rapidly begin to degrade when come in direct contact with aluminum oxide (Al2O3). 20-ketosteroids reaches a high degree of degradation (100% degradation) after addition of Al2O3 to an aerosolized formulation containing 20-ketosteroids. The '273 patent and '985 patent suggest the use of epoxy-phenolic lacquer or glass as an inert surface to minimize the degradation. Notably, the '985 patent states “the use of certain antioxidants such as ascorbic acid and ascorbyl palmitate (but not vitamin E) appeared to enhance chemical stability, while the use of oleic acid appeared to reduce chemical stability.” (See, the '985 patent, col. 12, lines 2-5). Thus, the '985 patent suggests that the 20-ketosteroid degradation in the presence Al2O3 is inhibitable by anti-oxidants.
We surprisingly discovered that a liquid formulation comprising isopropyl myristate and desoximetasone suffers from oxidation of desoximetasone. The liquid formulation, even when stored with an inert surface (e.g., glass or canister) begins to deteriorate (i.e., formation of an oxidized impurity) when subjected to accelerated storage conditions (e.g., 40° C., 75% relative humidity for 3 months), indicating unsuitability of the product. Although present in small amounts, the level of oxidized impurity (after long-term storage) exceeds the qualification threshold and identification threshold calculated based on the maximum daily dosage. (See, ICH Guidance for Industry Q3B® Impurities in New Drug Products, November, 2003).
There is a continuing need for developing an aerosolized formulation of desoximetasone and isopropyl myristate that contains minimum acceptable levels of oxidized impurity. Prior art endeavors in this field have fallen short because no stable aerosolized formulations comprising desoximetasone and isopropyl myristate have been identified. The present invention meets this need by providing the use of a stabilizing agent in an aerosolized formulation suitable for long-term storage.